Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is incurable with current therapies. Additionally, certain subsets of CLL patients including del(17p13.1) and those with ZAP-70 un- methylated (ZAP-70+) disease do not respond well to therapy and have a shorter overall survival. Unlike CML, where targeted therapy toward a single disease-specific fusion kinase is possible, in CLL there has been no single disease-specific targets identified. Recent studies, however, have identified B-cell receptor (BCR) signaling including the PI3-kinase, NF-?B, and MAPK/ERK are constitutively active in the lymph node and bone marrow compartment of CLL where disease expansion occurs suggesting that this may be a potential target in CLL. Additionally, patients with ZAP-70+ disease have enhanced BCR signaling. Proximal BCR signaling results in activation of the Bruton agammaglobulinemia tyrosine kinase (Btk) and genetic loss of this kinase by mutation or deletion in mice or humans produces predominately a B-cell defect. Based upon this, we were first to pursue and demonstrate that the orally bioavailable, irreversible Btk inhibitor ibrutinib (PCI-32765) promotes direct apoptosis, inhibits cell proliferation, and blocks microenvironment stromal signals important to CLL cell survival. In conjunction our group has worked closely with Pharmacyclics to perform the first phase Ib/II study of ibrutinib in CLL where 90% of patients had clinical benefit. Therapy has been well tolerated and the estimated progression-free survival rate is 86% at 1 year in relapsed patients independent of del(17p) and improved outcome in those with ZAP-70+ disease. This proposal builds upon this early experience of ibrutinib by performing a more definitive phase II trial in relapsed CLL with a separate cohort of del(17p13.1) patients that includes pharmacodynamic experiments aimed at identifying subsets of patients most likely to gain durable remissions with ibrutinib monotherapy and also to study the features of CLL cells not eliminated with this treatment at 12 months. The specific aims of our proposal include: 1) To perform a phase II clinical trial of ibrutinib to determine the response and 2-year PFS among patients having versus lacking del(17p13.1) and the long-term toxicity of this agent administered as a continuous therapy; 2) To perform baseline and serial pharmacodynamic studies to determine if traditional genomic features, select BCR activation markers, and changes in miR marker expression are predictive for response and 2-year PFS; and 3) To perform studies derived from samples from patients participating in both this and the earlier completed single agent ibrutinib trial to determine the biologic features of tumor cells not cleare from the blood by 12 months and pharmacologic strategies to eliminate these. At completion of this proposal, we will have determined the efficacy of ibrutinib in relapsed del (17p13.1) CLL while also identifying features predictive of single agent activity of this agent and also of tumor cells not effectively eliminated by ibrutinib. These will guide future combination studies with Ibrutinib that has great potential to completely change the treatment paradigm of CLL.